A compound designated as FK506 or FR-900506 is well known to have a potent immunosuppressive activity and is usable as an agent for the prophylaxis and treatment of rejection by organ transplantation and autoimmune diseases (for example, Japanese Patent Unexamined Publication No. 14818/1986).
However, the activity is so potent that the determination of the optimal dose is of utmost importance and administration of an amount capable of inducing effective immunosuppressive activity without side effects is extremely important.
Later studies revealed that the immunosuppressive action of FK506 is caused by the binding with an intracellular FK506 -binding protein (hereinafter indicated as FKBP) having similar activity to peptidylprolyl cis-trans isomerase [for example, Nature, 357, 692-694 and 695-697 (1992)].
FKBP is known to include several types depending on the molecular weight, such as FKBP-12 (molecular weight 12 KDa), FKBP-13 (molecular weight 13 KDa), FKBP-25 (molecular weight 25 KDa), FKBP-56 (molecular weight 56 KDa), FKBP-80 (molecular weight 80 KDa) and the like, and their structures have been already identified.
See, for example, Nature, 341, 755-757 and 758-760 (1989), J. Am. Chem. Soc. 113, 1409-1411 (1991), Proc. Natl. Acad. Sci., 88, 6229-6233 (1991) and the like.
Also, the production of an FKBP having a molecular weight of 11,819 daltons and 107 amino acids by genetic engineering has been already reported [Nature, 346, 671-674 (1990)].
It has also been reported that FK506 most strongly binds with FKBP-12 from among those FKBPs and its affinity constant (Kd) is 0.4 nM, and that FKBP-12 is present in large amounts not only in lymphocytes but also in various tissues inclusive of erythrocytes [Trans. Proc. 23 (6), 2760-2762 (1991)].
In view of the fact that, when FKBP-12 is given to mouse MLR system together with a certain amount of FK506, the immunosuppressive effect of FK506 is inhibited in proportion to the amount of the FKBP-12 added, FK-506 will be bound with FKBP-12 in plasma if it is present in blood, and the immunosuppressive effect cannot be obtained to the degree expected from the concentration of FK506 in plasma. Considering that erythrocytes of patients who underwent operation lyse and FKBP-12 in erythrocytes circulates through plasma, and that patients show different sensitivities, there has been a demand for the development of a technique which enables precise assay of FKBP level in plasma, whereby patient's sensitivity to FK506 is presumed and more desirable FK506 level in plasma can be determined.